Project Summary/Abstract Obesity and alcoholism are two of the most prevalent chronic diseases in the United States. These two diseases may be linked as obesity and alcoholism share common behavioral characteristics, such as binge intake, and are thought to utilize overlapping neural mechanisms. Additionally, obesity and alcoholism promote deficits in insulin and glucose metabolism, early predictors of Type II diabetes. The goal of this project is to understand how diets high in fat may interact with alcohol to worsen development and progression of both alcoholism and diet-induced obesity related metabolic dysfunction in mouse models. Specifically, we will examine how eating patterns can produce binge-type high fat diet food intake that may cross-sensitize to binge alcohol consumption in a novel behavioral model of co-morbid diet and ethanol interactions in mice. We will then examine the neurocircuitry involved in these binge intake patterns and determine the mechanisms by which high fat diets and alcohol modulate critical brain cell populations. Based on our preliminary data, we propose that high fat diet and alcohol consumption increase neuronal activation in the central nucleus of the amygdala via modulation of neuroimmune cell function. Finally, we will examine the impact of co-morbid high fat diet and alcohol consumption on insulin and glucose function and metabolism. In doing so, we will determine the mechanisms by which key neurocircuitry involved in the central control on insulin release are altered by high fat diet and alcohol. Specifically, we will be examining the mechanisms by which high fat diet and alcohol consumption inhibit the activity of neuronal populations in the dorsal motor nucleus of the vagus nerve that project to the pancreas and how this cell population is modulated by central amygdala inputs. These research questions will be tested with a novel combination of electrophysiologic, immunohistochemical, opto- and chemo- genetic, behavioral, and whole-animal physiology methods not typically seen within a single application and examine diet and alcohol changes from the cellular level to whole animal function. These studies will be of significant interest to the mission of the National Institute of Alcohol Abuse and Alcoholism, and are of important relevance to FOA PA-17-211. Successful completion of these studies will provide new understanding of the mechanisms involved in the disease progression of obesity and alcoholism as well as uncover new potential targets for the treatment of both disorders, both singularly and in co-morbid situations.